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Fast Rac1 activation cycles at the lamellipodium tip - Current Biology, sept. 2019

Fast Rac1 activation cycles at the lamellipodium tip - Current Biology, sept. 2019

Transient Activations of Rac1 at the Lamellipodium Tip Trigger Membrane Protrusion

The spatiotemporal coordination of actin regulators in the lamellipodium determines the dynamics and architecture of branched F-actin networks during cell migration. The WAVE regulatory complex (WRC), an e-ector of Rac1 during cell protrusion, is concentrated at the lamellipodium tip. Thus, activated Rac1 should operate at this location to activate WRC and trigger membrane protrusion. Yet correlation of Rho GTPase activation with cycles of membrane protrusion previously revealed complex spatiotemporal patterns of Rac1 and RhoA activation in the lamellipodium. Combining single protein tracking (SPT) and super-resolution imaging with loss- or gain-of-function mutants of Rho GTPases, we show that Rac1 immobilizations at the lamellipodium tip correlate with its activation, in contrast to RhoA. Using Rac1 e-ector loop mutants and wild-type versus mutant variants of WRC, we show that selective immobilizations of activated Rac1 at the lamellipodium tip depend on e-ector binding, including WRC. In contrast, wild-type Rac1 only displays slower di-usion at the lamellipodium tip, suggesting transient activations. Local optogenetic activation of Rac1, triggered by membrane recruitment of Tiam1, shows that Rac1 activation must occur close to the lamellipodium tip and not behind the lamellipodium to trigger e-cient membrane protrusion. However, coupling tracking with optogenetic activation of Rac1 demonstrates that di-usive properties of wild-type Rac1 are unchanged despite enhanced lamellipodium protrusion. Taken together, our results support a model whereby transient activations of Rac1 occurring close to the lamellipodium tip trigger WRC binding. This short-lived activation ensures a local and rapid control of Rac1 actions on its e-ectors to trigger actin-based protrusion.

Amine Mehidi, Olivier Rossier, Matthias Schaks, Anaël Chazeau, Fabien Biname, Amanda Remorino, Mathieu Coppey, Zeynep Karatas, Jean-Baptiste Sibarita, Klemens Rottner, Violaine Moreau.

- Current Biology, Volume 29, ISSUE 17, P2852-2866.e5, September 09, 2019
- See the press release here
- Contact: Grégory Giannone